PREPARATIONS OF THE HORMONES OF THE CEREALS OF THE ADRENALS (CORTICOSTEROIDS, GLUCOCORTICOIDS, GLUCOCORTICOSTEROIDS)
This is a very important group of drugs that is widely used in clinical practice.
There are two main groups of hormones:
1. Mineralocorticoid hormones (corticosteroids, which predominantly cause a sodium-retaining effect): a) aldosterone; b) 11-deoxycorticosterone.
2. Glucocorticoid hormones (corticosteroids that affect glycogen deposition in the liver): a) cortisol (hydrocortisone); b) cortisone; c) 11-deoxycortisol; d) 11-dehydrocorticosterone.
In addition to these groups, a group of sex hormones is distinguished:
– androsterone;
– androstenediol;
– estrone and progesterone.
These hormones are natural, natural. Currently, pharmacological preparations are synthesized – full analogues of these hormones.
PREPARATIONS OF NATURAL HORMONES – GLUCOCORTICOIDS
It should be said that synthetic drugs – analogues of natural glucocorticoid hormones also have a weak mineralocorticoid activity (retention of sodium ions, water, loss of potassium ions and calcium). In recent years, a whole series of synthetic hormonal preparations have been created, having, in the main, only glucocorticoid activity:
1), prednisone, prednisolone, methylprednisolone, mazipredon;
2) dexamethasone (most active in rheumatism);
3) triamcinolone;
4) beclomethasone ( bekotid ), flunisolide ( ingacort );
5) betamethasone;
6) Flumetazon, flucortolone, fluocinolone.
7) budesonide and others.
New drugs are almost completely devoid of mineralocorticoid activity. Pharmacological effects of synthetic agents coincide with the physiological. At the same time, the pharmacological effect of all glucocorticoids on directionality is almost the same. They stand out in response to stress, adapting the body, mobilizing and increasing its resistance. Therefore, glucocorticoids have a diverse effect on all types of metabolism: protein, carbohydrate, fat.
I. Effect of glucocorticoids on carbohydrate metabolism:
– in peripheral tissues, for example, in muscles, protein synthesis from amino acids is inhibited ( antimetabolic effect), the level of amino acids in the blood increases significantly;
– in the liver, glucose synthesis from amino acids is stimulated ( gluconeogenesis ), protein synthesis in the liver and kidneys is reduced;
– absorption, assimilation and utilization of glucose by the tissues decreases, which leads to an increase in the level of glucose in the blood (hyperglycemia), and the resorption of carbohydrates in the gastrointestinal tract decreases.
Ii. Effect of glucocorticoids on protein metabolism:
– glucocorticoids enhance the mobilization of amino acids from tissues, in particular from skeletal muscles, and inhibit protein synthesis, in particular in bones (osteoporosis).
Iii. Effect of glucocorticoids on fat metabolism:
– glucocorticoids play a “resolving” role in the mobilization of fat from the depot (which also occurs under the action of adrenaline and growth hormone). With long-term use of hormones, redistribution of fat occurs. In some tissues there is an increase in lipolysis processes (limbs), while the amount of free fatty acids in the blood plasma increases, and in other tissues there is an increase in lipogenesis processes (upper torso, face – “moon face”, neck – “buffalo hump”). In the blood, there is hypercholesterolemia.
Iv. Influence of glucocorticoids on water – electrolyte metabolism:
– natural and first synthetic glucocorticoids have a weak sodium-retention, as well as calcium and potassium-deducing effect. Therefore, when prescribing a patient large doses (more than 300 mg / day), sufficient sodium retention is observed.
New synthetic analogs of natural glucocorticoids do not possess this activity and even, on the contrary, can cause a significant loss of sodium ions in the urine.
EFFECTS OF GLUCOCORTICOIDS ON INFLAMMATION
Glucocorticoid hormones inhibit all the main phases of inflammation: alteration, exudation and proliferation. In this regard, there are many hypotheses.
The following are most acceptable:
1. Glucocorticoids stabilize cell membranes and lysosomes (membrane – stabilizing effect), thereby limiting the release of enzymes from them and, as a result, tissue damage (during inflammation, hypoxia, shock, burns).Glucocorticoids help to maintain the integrity of the cell membrane even in the presence of toxins, which reduces cell swelling.
2. Glucocorticoids enhance the synthesis of lipomodulin – an endogenous phospholipase A-2 inhibitor , thereby inhibiting its activity. Phospholipase A-2 mobilizes arachidonic acid from cell membrane phospholipids and the formation of metabolites of this acid (prostaglandins and leukotrienes ), which play a key role in the process of inflammation.
In addition, glucocorticoids stimulate the synthesis of the intercellular substance – hyaluronic acid, which reduces the permeability of the vascular wall. The decrease in exudation is also associated with a decrease in histamine secretion, as well as a change in the sensitivity of adrenergic receptors to catecholamines (adrenaline). The vascular tone increases, and the permeability decreases.
Inhibition of proliferation by glucocorticoids is associated with a decrease in protein synthesis and a decrease in leukocyte counts in the tissue. There is a restriction of chemotaxis, spontaneous migration.
Thus, corticosteroids do not affect the cause of inflammation; therefore, their anti-inflammatory activity is non-specific and is observed both in systemic and local application.
ANTIALLERGICAL AND IMMUNODEPRESSIVE EFFECT OF GLUCOCORTICOIDS
Glucocorticoids cause both absolute and relative T- lymphocytopenia , that is, inhibit cellular immunity.
Glucocorticoids inhibit the graft rejection reaction, as they suppress the delayed-type hypersensitivity reaction.
Moreover, the hormones of this group do not alter the production of antibodies by B-lymphocytes, as well as the formation of immune complexes.
Glucocorticoids inhibit phagocytosis and the digestive function of microphages and macrophages.
In addition, glucocorticoids increase the sensitivity of the adrenoreceptor
tori to catecholamines (permissive effect).
Thus, given that glucocorticoids have an immunosuppressive effect associated with the effect on various stages of the immune response, it becomes clear why glucocorticoids increase the body’s susceptibility to various bacterial, fungal, viral and parasitic infections.
INFLUENCE OF GLUCOCORTICOIDES ON THE BLOOD SYSTEM
Glucocorticoid hormones cause rapid lysis of lymphoid tissue and lymphopenia on the background of general leukocytosis. There is a decrease in the number of eosinophils.
However, at the same time, glucocorticoids contribute to an increase in the level of platelets and red blood cells.
It should be remembered that in addition to all the above effects, glucocorticoids have another purely pharmacological effect – they reproduce the effects of natural hormones when they are deficient in the body.
Indications for use of drugs glucocorticoid hormones:
1. As a means of replacement therapy for adrenal insufficiency (with Addison’s disease) in combination with mineralocorticoid).
2. As a means of anti-inflammatory therapy:
– in collagenoses (diffuse connective tissue diseases, for example, rheumatism, rheumatoid arthritis, Bechterew’s disease, systemic lupus erythematosus ); Usually, according to this indication, glucocorticoids are prescribed in combination with other drugs in the most severe cases:
– with severe glomerulonephritis;
– in severe forms of hepatitis;
– in case of eye diseases of inflammatory etiology (interstitial keratitis, conjunctivitis, iritis, iridocyclitis, sympathetic ophthalmia, etc.);
– with skin diseases (inflammatory dermatosis, eczema, psoriasis, etc.).
3. As a means of antiallergic therapy:
– with bronchial asthma;
– With autoimmune hemolytic anemia, thrombocytopenia.
4. In order to reduce the permeability of the vascular wall, membranes in general:
– With acute swelling of the brain and lungs;
– with toxic and toxicoseptic forms of pneumonia (especially in children);
– toxic , toxicoseptic lesions of the gastrointestinal tract of staphylococcal and viral etiology;
– at complex therapy of shock (any).
5. In order to influence the blood system:
– with anemia, thrombocytopenia;
– with lymphoid leukemia, lymphoma;
– to suppress the graft rejection reaction during transplantation of organs and tissues.
With all indications it should be remembered that glucocorticoids do not act on the main triggers of the development of these pathologies, but only suppress the symptoms. In this regard, glucocorticoids – means of palliative (maintenance) therapy.
TACTICS OF THERAPY BY GLUKOCORTICOID PREPARATIONS
Glucocorticosteroid therapy varies depending on the clinical tasks, methods of drug administration, the size of the doses used, the duration and treatment regimens. Optimal dosing regimens and the choice of route of administration are aimed at increasing the effectiveness of therapy and at reducing the risk of adverse effects.
Among the methods of drug administration the most frequent is oral. In case of emergency therapy, intravenous administration of drugs is used. Intramuscular use of special forms of prolonged medications, however, it is necessary to take into account undesirable effects that often occur with this type of drug administration:
1) atrophy of muscle tissue;
2) atrophy of adipose tissue at the injection site.
In addition, this type of administration does not allow modulating the circadian rhythms of the body, which increases the risk of suppressing the hypothalamic-pituitary system.
In the treatment of patients with bronchial asthma, an inhalation form of the introduction of aerosol preparations ( becotide , Ingacort ) is used. In this case, the drugs have a strong local effect with little systemic effect. The lack of systemic action due to the fact that the absorption almost does not occur. Thus, it is possible to avoid many of the side effects of systemic corticosteroid therapy.
Thus, the use of hormonal drugs in case of acute need allows us to treat them as ordinary drugs. The use of dosage forms of glucocorticoids for local use (ointments, creams, aerosols) is also practically not dangerous. Long-term use of glucocorticoids is justified only in the case of severe pathology. When prescribing tablets dosage forms must take into account chronobiological peculiarities and patterns. We need to strive for the appointment of drugs through the day, which reduces the risk of oppression of the adrenal cortex and nonspecific resistance of the organism to infection. In case of unacceptability of this method of administration, it is best to administer a daily dose once in the morning.
In terms of treatment, there are two types of glucocorticoid therapy:
1. Short-term (intensive) glucocorticosteroid therapy. The drugs are administered once or for several days.
This type of therapy is applied for health reasons (shock of any etiology, systemic allergic reactions, intoxication). At the same time, maximum dosages are necessary. The withdrawal syndrome in this case is not marked.
2. Long-term (maintenance) glucocorticosteroid therapy.
This type of therapy is used in the treatment of patients with subacute or chronic course of the disease, with exacerbation of chronic pathology.
PECULIARITIES OF REDUCING DOSAGE AND CANCELLATION OF GLUCOCORTICOIDES
The use of prednisolone in a dose of more than 10 mg already after one week causes functional insufficiency of the adrenal cortex, lasting for 1-2 days, and many months of therapy in doses of more than 5 mg in half of patients leads to structural atrophy of the adrenal cortex.
With a decrease in the daily dose of glucocorticoids, it is necessary to take into account that the full replacement effect of endogenous hormones has doses of drugs (for example, prednisolone) exceeding 10 mg. Therefore, prednisolone dose reduction to 10-15 mg / day with a higher one can be carried out quickly. However, in the future, everything must be done slowly, usually not faster than 2, 5-5 mg for 5-7 days.
Within six months after the cancellation of long-term glucocorticosteroid therapy in cases of stress, the adherence of infectious diseases, hormonal preparations should be reappointed.
Before hirugicheskoy operation (even if a tooth extraction, endoscopic procedures), the patient should be given 25-30 mg of prednisone per repeat hour before surgery and then every six hours during the day.
COMPLICATIONS, SIDE EFFECTS OF GLUKOCORTICOSTEROID TREATMENT
The number of complications and side effects is very high, about 20-100%, including:
1. The phenomena of hyperglycemia (“steroid diabetes”).
In this regard, a diet with carbohydrate restriction is necessary, if necessary, insulin is used.
2. The decrease in protein synthesis, which is implemented in the form
– muscle pain, increased muscle fatigue;
– osteoporosis;
– delayed wound healing;
– teratogenic effects;
– the lag of children in development and growth (when using glucocorticoids for six months or more);
– decrease in absorbability (gastric mucosa suffers) of calcium and phosphorus ions, which in children leads to rickets;
– exacerbation or even the appearance of new ulcerations
intestinal mucosa (inhibition of proliferation processes);
– clouding of the lens and the development of cataracts. Especially with prolonged use of glucocorticoids in children;
– increased irritability in children;
– increase blood pressure, salt and fluid retention, especially in adolescents;
– redistribution of fat (“moon face”, “buffalo hump”);
– reduction of immunity, immunosuppressive effect, which is realized by an increase in colds.
3. It is possible the development of withdrawal syndrome, especially with a sharp withdrawal of drugs (adrenal insufficiency). Therefore, after long-term administration of glucocorticoids , the dosage should be reduced very slowly. It is possible to stimulate the adrenal cortex by administering ACTH or its synthetic analogue, corticotropin.
Contraindications to the appointment of glucocorticoids :
1. Diabetes.
2. Osteoporosis.
3. Pregnancy.
4. Peptic ulcer disease.
5. The presence of a wound process.
6. Hypertensive heart disease.
7. Epilepsy.
All listed contraindications are relative.
Currently, in order to prevent complications associated with the resorptive action of glucocorticoids , a large number of their topical dosage forms have been created. For example, ointments manufactured by Gedeon Richter (Hungary): apulein ( budesonide ), aurobin , dermozolon , depersolone ( mazipredon ), hydrocortisone, prednisolone, fluorocort ( triamcinolone ), mycozolone ; eye drops: prednisone; eye ointment: hydrocortisone and others.
Large distribution receive combined ointments containing not only glucocorticoids , but also substances that have an antiseptic effect (for example, “Aurobin”); antifungal and antimicrobial action (“Micozolon” and “Dermozolon”), etc.
PREPARATIONS OF HORMONES OF THE THYROID GLAND AND ANTI-THYROID MEANS
Under the influence of thyroid-stimulating hormone of the adenohypophysis, the follicular cells of the thyroid gland produce and enter into the blood two main iodine-containing hormones:
1) thyroxin (T4);
2) triiodothyronine (T3).
Thyrocalcitonin ( calcitonin ) is produced in the interstitial cells of the thyroid gland . There are four iodine atoms in the thyroxine molecule, and three in the triiodothyronine molecule . T4 and T3 are in plasma, partially in protein-related and partially in free states. Content in plasma T4 is reflected by the amount of iodine plasma bound to proteins. Free hormones are physiologically active, while the bound fraction serves as a reserve. Despite the fact that in the thyroid gland thyroxin is synthesized in greater quantities than triiodothyronine , the latter has a greater (fivefold) activity against most tissues of the body. In peripheral tissues, about 30% of T4 goes to T3.
In the life of these hormones, there are three main stages that are controlled by the TSH of the adenohypophysis:
1. Capture gland iodides.
2. Connection of iodine with the amino acid tyrosine, which is contained in the thyroglobulin molecule , with the formation of sequentially mono- and diiodotyrosine .
3. When two diiodotyrosine molecules are joined , thyroxin (T4) is formed, and when monoiodotyrosine and diiodotyrosine are combined , triiodothyronine (T3 ) is formed.
At the last stage, hormones are released into the blood.